The objectives of the proposed research are to identify and study factors that control drug reinforced behavior using genetically divergent mouse and rat populations. The methodology and principles of operant conditioning and pharmacogenetic analysis will be used. The studies will be limited to conditions in which the drug is taken orally and functions as a positive reinforcer. The focus will be on the variables that control drug reinforced behavior, especially genetic variables, but also including pharmacological variables and environmental variables, e.g., drug concentration and fixed ratio size. The proposed studies are important because (1) drug intake will be examined under conditions in which it is taken orally and functions as a reinforcer; (2) they will explore genetic and environmental factors and their interactions which contribute to drug self-administration; and (3) the use of genetically defined animals will provide information concerning the degree to which genetic factors regulate drug-seeking behavior. These studies complement ongoing investigations into the genetic factors affecting the acute response to drugs of abuse and will contribute the determination of traits with common or independent genetic backgrounds. In addition these studies are important in the development of predictive models of self-administration behavior and the determination of individual genotypes at risk for the acute toxic effects of the drug. Recent findings included 1) Developing oral cocaine self-administration procedures, 2) Defining genetic differences in reinforcement from opiates; and 3) Determining common and independent genetic factors in the acute, toxic and reinforcing effects of opiates.